Molecular Diagnosis of Inherited Movement Disorders Movement Disorders Society Task Force on Molecular Diagnosis

State of the Art Review

Thomas Gasser, MD,1,7 Susan Bressman, MD,2 Alexandra Du¨rr, MD, PhD,3 Joseph Higgins, MD,4 Thomas Klockgether, MD,5 and Richard H. Myers, PhD6

1Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-University, Munich, Germany 2Department of Neurology, Beth Israel Hospital, New York, New York, USA 3De´partement de Ge´ne´tique, Cytoge´ne´tique et Embryologie, INSERM U289, Hoˆpital de la Salpeˆtrie`re, Paris, France 4Laboratory of Clinical Neurogenetics, NYSDOH, Albany, New York, USA 5Department of Neurology, University of Bonn, Bonn, Germany 6Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA 7Center of Neurology, Department of Neurodegenerative Disorders and Hertie Institute of Clinical Brain Research, University of Tu¨bingen, Tu¨bingen, Germany

Abstract: This review is designed to provide practical help for of movement disorders are considered separately. © 2002 the clinical neurologist to make appropriate use of the possi- Movement Disorder Society bilities of molecular diagnosis of inherited movement disor- Key words: Huntington’s disease; Parkinson’s disease; par- ders. Huntington’s disease, Parkinson’s disease and parkinso- kinsonism; autosomal recessive ataxias; autosomal dominant nian syndromes, ataxias, Wilson disease, essential tremor, cerebellar ataxias; Wilson disease; essential tremor; primary dystonias, and other genetic diseases associated with a variety torsion dystonia; genetic testing

OVERVIEW further insight into the molecular pathogenesis of these Recent progress in molecular genetics has greatly ex- disorders. Eventually, new approaches towards therapy panded our knowledge of the molecular basis of many and prevention will emerge. Today and in the years to inherited neurological diseases. The chromosomal posi- come, keeping apace of the rapid advances in neuroge- tion of a large number of genes that, when mutated, can netics will be a challenge to neurologists everywhere. cause neurological dysfunction, is now known. In many Molecular genetic techniques have been particularly valuable in defining and classifying heterogeneous inher- cases, the genes themselves and their disease-causing ited movement disorder syndromes, such as the dysto- mutations have been identified. This increasing wealth of nias, and the spinocerebellar ataxias. knowledge has allowed the reclassification of a number In clinical practice, the availability and limitation of of formerly heterogeneous clinical syndromes and pro- molecular diagnosis depends on our present knowledge vides novel diagnostic possibilities. It allows the charac- of the molecular genetic basis of the respective disease or terization of pathologic gene products, thus providing group of diseases, but also on the degree of genetic complexity of the disorders under investigation. Some diseases, such as Huntington’s disease, are caused by a *Correspondence to: Thomas Gasser, MD, University of Tu¨bingen, 1 Hertie Institute for Clinical Brain Research, Hoppe-Seyler Str. 3, 72076 specific mutation in a single gene, and routine molecular Tu¨bingen, Germany. E-mail: [email protected] diagnosis can be provided by a simple PCR-based assay. Received 14 January 2002; Revised 12 April 2002; Accepted 16 July In other cases, however, for example in dopa-responsive 2002 dystonia, many different mutations can be found (allelic heterogeneity). Depending on the size of the gene, this

3 4 T. GASSER ET AL. may render molecular diagnosis very costly and time- testing, and genetic counseling for all asymptomatic fam- consuming and some mutations, like those situated in the ily members needs to be done first. If the treating neu- introns affecting RNA-splicing or in regulatory se- rologist does not have thorough experience with inher- quences upstream of the coding region, may be difficult ited disorders, referral to an experienced counselor from to detect on routine sequencing. a department of human genetics or another genetic coun- Despite the fact that only a small percentage of inher- seling unit is strongly advised. In most situations, genetic ited movement disorders can be treated efficiently, mo- testing should not be performed until adequate counsel- lecular diagnosis is increasingly important, because it ing has been provided. may provide valuable information for the affected indi- Ethical dilemmas may arise from molecular testing, viduals and their families in order to make informed concerning matters of employment, insurance, and gen- choices on life and family planning. If genetic testing is eral life planning, that must be dealt with carefully on an able to identify the cause for neurological symptoms, individual basis.2 subsequent exhaustive costly investigations will be In the case of predictive testing, psychological coun- avoided. seling by appropriately trained persons is essential before This review is designed to provide practical help for testing and again after results have been disclosed. the clinical neurologist to make appropriate use of the possibilities of molecular diagnosis of inherited move- Informed Consent. ment disorders. It should be emphasized that molecular As is true for all diagnostic procedures, the essential testing may be a procedure of far-reaching consequences, prerequisite for molecular diagnosis is the informed and both for the individual affected and for the entire family. voluntary consent of the patient. Therefore, the neurol- It should, therefore, be performed only after careful ogist should establish that the patient or a lawful surro- consideration, including a genetic counseling process, in gate is capable of comprehending relevant information accordance with local regulations, which may differ con- and is exercising informed choices. Molecular genetic siderably in different parts of the world. It may also be diagnostic tests should not be performed at the request of important to contact your area’s Department of Health members of the patients’ families or other third parties before ordering a diagnostic genetic test to confirm that (e.g., insurers, employers) without the express written the laboratory is approved to perform the test. consent of the patient.

General Principles of Molecular Diagnosis Confidentiality. The primary goal of molecular diagnosis is to provide Test results suggesting that patients or family mem- help for the individual patient, client and/or their fami- bers carry mutations that indicate or predict a major lies. Reducing the prevalence of inherited disorders in a neurological disorder or a susceptibility to a neurological population or in subsequent generations may be a sec- disorder are highly sensitive. Therefore, rigorous mea- ondary effect, but must never be allowed to guide the sures to ensure confidentiality should be taken. Test process of genetic counseling and diagnosis. results should never be disclosed to a third party without explicit written consent from the patient or their lawful Genetic Counseling. surrogates. It must always be kept in mind that the molecular genetic diagnosis of an inherited disorder affects not only Presymptomatic Diagnosis. the patient, but also the entire family. Therefore, genetic The identification of disease genes allows presymp- counseling is an essential component of the diagnosis of tomatic (predictive) diagnosis in many cases. There may inherited disorders. Sensitive and informed counseling be risks associated with presymptomatic testing and provides patients and families with a foundation for these include an adverse emotional response, restricted decisions about testing. Patients should be counseled access to insurance, discrimination in employment, and concerning the clinical features and course of their dis- concerns about confidentiality. The decision for predic- ease as well as over potential consequences for the fam- tive testing should be undertaken only after appropriate ily, taking into consideration the most important genetic counseling to permit an informed decision concerning parameters such as mode of inheritance and penetrance. the risks and benefits for the individual. Guidelines for Even if the test is negative, a genetic etiology is not presymptomatic diagnosis have been issued by the Inter- excluded. If the test is positive, a diagnosis is secured but national Huntington’s Disease Society and the World this diagnosis impacts on other at-risk family members. Federation of Neurology (WFN) research group for Hun- These members, even if asymptomatic, may wish carrier tington’s disease.3,4 These guidelines, which include ex-

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 5 tensive pre- and post-test counseling and thorough psy- predictive testing for HD was the most widely used chological support during the extensive process, should application for indirect molecular diagnosis. As more be followed in all cases of presymptomatic diagnosis. and more disease genes are identified, direct mutational Generally, presymptomatic testing should be provided analysis has become increasingly important. within the setting of a department of Human Genetics only. The same is true for prenatal diagnosis. If no clear Practical Approach to Molecular Diagnosis. therapeutic consequences can be envisioned, presymp- The patient confirms his informed consent to the pro- tomatic diagnosis should not be performed in minors. cedure in writing. Usually, 10 to 20 ml of whole blood (EDTA or ACD for lymphocyte lines) are sufficient. The Principles of Molecular Diagnosis blood can be sent by mail to the laboratory without “Direct” Molecular Diagnosis, Mutational Analysis. freezing or refrigeration. A delay of 3 to 5 days before DNA extraction is acceptable. It is obviously crucial that If the gene causing a neurological disorder is known, the tubes are clearly labeled, and that the clinical infor- direct molecular diagnosis can be performed by muta- mation including family history and the informed con- tional analysis. Only DNA from the affected individual is sent are contained within the shipment. required. Usually, DNA is extracted from peripheral blood leukocytes, and exonic sequences, which are INHERITED MOVEMENT DISORDERS known to harbor mutations in the particular disorder under investigation, will be amplified by use of the HUNTINGTON’S DISEASE polymerase chain reaction (PCR). Depending on the type of the mutation, it will then be detected either directly by Richard H. Myers and Judith A. Sinsheimer gel electrophoresis (e.g., in the case of trinucleotide Huntington’s disease (HD), a dominantly transmitted repeat expansions), gel electrophoresis following diges- neurodegenerative disorder involving the basal ganglia tion by a suitable restriction enzyme (if a particular and cerebral cortex, typically strikes in mid-life but onset mutation alters a cutting site (restriction site) of a par- can occur at any age. The characteristic symptoms of HD ticular enzyme), or direct sequencing. If a gene is very are involuntary choreiform movements, cognitive im- large (genes with 30 and more exons are not uncommon) pairment, mood disorders, and behavioral changes. The and mutations are scattered throughout the entire gene, nature of the genetic defect, an unstable expanded CAG direct mutational analysis can be very costly and time- repeat within the coding region of a novel gene, explains consuming. In these cases, routine sequence analysis is many of the genetic features of the disorder, including sometimes offered only for portions of a gene, where the variability in age at onset, tendency of juvenile dis- mutations may be clustered. ease to be inherited from fathers, and sporadic appearance of new mutations to HD.1 “Indirect” Molecular Diagnosis. A single diagnostic procedure can be performed to Knowledge of the chromosomal position of a disease confirm or rule out the presence of a mutation associated gene allows molecular support for the diagnosis, even if with HD. Normal chromosomes possess from 6–26 CAG the disease gene itself is unknown or if analysis is repeats that are inherited in a Mendelian fashion. HD unfeasible. “Indirect” molecular diagnosis is limited to chromosomes have from 40 to over 100 CAG-units. risk determination for an individual in whose family an Exceptionally, alleles with 36–39 repeats can be found in inherited neurological disease has already been diag- unaffected elderly relatives of sporadic de novo cases of nosed clinically or molecularly. The method is based on the disease. The identification of this genetic defect in the analysis of DNA polymorphisms (“markers”) known HD makes it possible to offer a direct DNA test through to be in close neighborhood (closely linked) to the dis- polymerase chain reaction (PCR) amplification of HD ease gene under investigation. Determination of the CAG repeat. The length of the expanded CAG repeat is marker alleles in healthy and affected family members strongly inversely correlated with the age at onset of the allows the identification of the disease gene–bearing disease. Nevertheless, any given expanded CAG repeat chromosome in this particular family. It must be empha- may be associated with a broad range of onset ages, sized that accurate clinical diagnosis in at least one indicating that the relationship of repeat size to onset age affected family member is an absolute prerequisite for is not sufficiently strong to be used clinically to predict this type of molecular diagnosis and there is a small but onset for subjects who are not yet symptomatic. definite error rate with this sort of linkage analysis. Until Currently four CAG repeat size ranges are recognized the gene for Huntington’s disease was identified in 1993, to be associated with varying disease risk in HD. These

Movement Disorders, Vol. 18, No. 1, 2003 6 T. GASSER ET AL. ranges have been defined by the “US HD Genetic Test- formed for persons with a neurological disorder consis- ing Group” (USHDGTG) and are derived from informa- tent with the HD diagnosis but absent family history tion derived from more than 1,000 HD tests and from because of early death of ancestors, non-paternity, or published sources. Nevertheless, the disease-related risk adoption. pertaining to the repeats in the 27 to 39 range has often Presymptomatic testing to determine the HD carrier been estimated from fewer than 10 observations at each status of individuals at risk for HD may be performed for repeat size and thus these risk estimates can be expected persons who request this information. Because there is to change with additional experience. no medical intervention to delay onset or lessen the severity of the disease, presymptomatic testing should be Normal: Repeat Sizes Up to 26 Units done cautiously.3,4,9 Often presymptomatic testing is Persons with repeats in this range neither develop HD sought when major life decisions are contemplated, such nor has there been a confirmed instance of a child inher- as marriage or childbearing. iting HD from a parent with a repeat in this range. Prenatal testing may be performed when one parent is known to carry the HD gene and the couple wants to Non-Penetrant with Paternal Meiotic Instability: determine the carrier status of the fetus. Genetic coun- Repeats of 27 to 35 Units seling to weigh the option of terminating the pregnancy Repeats in this range are rare and represent approxi- of a fetus bearing the HD gene is crucial. In some mately 1% of expanded alleles seen in HD testing pro- instances, individuals at risk for HD may request a pre- grams. There have been no confirmed reports of persons natal test when their carrier status is unknown. Tests that with repeats in this range expressing HD. There are, may reveal simultaneously that the parent and the fetus however, confirmed cases of paternally transmitted mei- are HD gene carriers can be emotionally difficult. Se- otic instability such that descendants of fathers with quential testing of the parent and then the fetus has the repeats in this range are known to have inherited an advantage of preventing some unnecessary prenatal test- expanded allele in the clinical range. ing when the parent is gene negative.

Reduced Penetrance with Meiotic Instability: PARKINSON’S DISEASE AND PARKINSONIAN Repeats of 36 to 39 Units SYNDROMES Repeats in this range are rare and represent approxi- Thomas Gasser mately 1 to 2% of expanded alleles seen in HD testing programs. Some persons with repeats in this range de- Familial Parkinson’s Disease velop HD and others live into their late 90s without evidence of the disease.5,6 There is evidence that pen- Until recently, the role of genetic factors in the etiol- etrance increases with increasing allele size in this range. ogy of Parkinson’s disease (PD) has not been widely recognized. Today, it is well known that mutations in HD: Repeats of 40 Units or Larger several genes are able to cause monogenically inherited Currently, it is believed that all persons with repeats in forms of Parkinson’s disease. the range of 40 or more will eventually develop HD. However, some individuals with repeats at the low end of PARK1: Parkinson’s Disease Caused by Mutations ␣ this range are reported to exhibit initial symptoms at ages in the Gene for -Synuclein older than common life expectancy and thus there may The discovery that mutations in the gene for ␣-synuclein be some reduced penetrance among carriers of 40 and 41 can cause an early-onset form of PD with autosomal-dom- repeats.7,8 inant inheritance is particularly interesting in light of the fact that the ␣-synuclein protein is one of the major com- Recommendations on the Use of Genetic Testing. ponents of the histopathologic hallmark of PD, the Lewy Genetic testing for Huntington’s disease is offered in body.10 Only two mutations have been identified so far: one three circumstances: Confirmatory and diagnostic test- causing an amino acid exchange (threonine for alanine) at ing, predictive testing, and prenatal testing. position 53 of the protein in an Italian and several Greek Confirmation of diagnosis by direct gene testing may families,11 and one substituting a proline for an alanine at be warranted when a clinical diagnosis of HD has been position 30 in a German pedigree.12 The phenotype resem- made but the presence of an expanded Huntington CAG bles idiopathic PD both clinically and neuropathologi- repeat has not been confirmed in an affected member of cally,13 with the exception of an earlier age at onset (mean the family. Similarly, diagnostic testing may be per- age at onset approximately 45 years).

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 7

Recommendations on the Use of Genetic Testing. Sporadic Parkinson’s Disease or Parkinson’s As mutations in this gene are exceedingly rare, se- Disease with Familial Clustering quencing is not routinely warranted in a clinical setting, The vast majority of cases with typical Lewy-body but may be possible in exceptional cases for research Parkinson’s disease is clearly not inherited in a simple purposes. mendelian fashion. Although a large number of genetic risk factors has been studied in this population, none of PARK2: Autosomal-Recessive Juvenile them has so far been confirmed beyond doubt, so they Parkinsonism cannot be used for risk-counseling in PD. Mutations in the parkin gene on chromosome 6 have Recommendations on the Use of Genetic Testing. first been identified in Japanese patients with an autoso- No genetic testing is available at present. mal-recessive syndrome of juvenile parkinsonism.14 The clinical syndrome is that of L-dopa–responsive parkin- Other Parkinsonian Syndromes sonism with early development of fluctuations and dys- Progressive Supranuclear Palsy (PSP). kinesias, but a relatively slow progression and a sus- tained good response to treatment. There may be Progressive supranuclear palsy (PSP) is a neurodegen- dystonia at onset of the disease in some cases. In the few erative disorder characterized by an akinetic rigid syn- cases that have come to autopsy, severe degeneration of drome, dementia, and supranuclear gaze palsy. It occurs as the substantia nigra is found, but no Lewy bodies, pos- a sporadic disorder in the vast majority of cases. Patholog- sibly indicating a molecular pathogenesis differing from ically, straight filaments consisting of hyperphosphorylated that of idiopathic Parkinson’s disease. Many different MAPtau-protein (“microtubule-associated protein”) are mutations, including exon deletions and point mutations found in neurons. Interestingly, the great majority of pa- have been identified. Mutations in the parkin gene appear tients with clinically probable PSP are homozygous for an to be much more frequent than those in ␣-synuclein. In a extended haplotype of DNA-polymorphisms within and series of 73 pairs of affected siblings, parkin mutations around the MAPtau gene.22,23 It is hypothesized that these have been identified in nearly 50% of families.15 In polymorphisms may be in linkage disequilibrium with an- sporadic patients, the prevalence of parkin mutations other, as yet undetected, DNA sequence variation in the largely depends on the age at onset: While the majority regulatory regions of the tau gene, altering its expression of patients with onset under 20 years of age (Ͼ70%) and pattern and thereby promoting aggregation of tau in straight 25% of those with onset in the third decade carry parkin filaments. mutations, these are only rarely found in patients with an As this haplotype is found in the homozygous state age at onset above 40.15 However, in exceptional cases also in a significant percentage of age-matched normal onset may be as late as 58.16 individuals, it can certainly not be the only determinant of tau pathology. However, lack of homozygosity for this Recommendations on the Use of Genetic Testing. haplotype practically excludes the diagnosis of “pure” Genetic testing can be offered in young-onset cases of PSP. Homozygosity for this haplotype has also been found L-dopa–responsive PD. However, the chance of detecting parkin mutations is probably only in the range of 2–5% in cases with corticobasal degeneration (CBD), a disor- in patients with onset under 40. It is much greater in der which is also associated with abnormal tau-accumu- those with onset under 30 and in those with a possible lation, further strengthening the suspected etiologic link recessive inheritance (more than one affected sibling). between these two disorders. Confirmation of this recessive form of PD may be help- Recommendations on the Use of Genetic Testing. ful in genetic counseling, as it renders transmission to the As the presence of the PSP-associated haplotype is not subsequent generation very unlikely. helpful in the diagnosis of an individual case of PSP, genetic analysis should be restricted to a research setting. Other Forms of Inherited Parkinson’s Disease No clinically useful genetic test can be offered to In other forms of familial parkinsonism (dominant: patients. PARK3 on chromosome 2p13,17 PARK4 on chromo- Frontotemporal Dementia with Parkinsonism some 4p,18 and PARK8 on chromosome 1219; recessive: Linked to Chromosome 17 (FTDP-17). PARK620 and PARK7,21 both on chromosome 1) no genetic testing is available as the respective genes have After Alzheimer’s disease, frontotemporal dementia not yet been identified. (FTD) is the most common neurodegenerative dementia.

Movement Disorders, Vol. 18, No. 1, 2003 8 T. GASSER ET AL.

TABLE 1. Hereditary ataxias with autosomal recessive inheritance

Disorder Symbol Locus Gene Mutation Ref. Friedreich’s ataxia FRDA 9q13-21.1 Frataxin Trinuc/Pm 29 Ataxia telangiectasia AT 11q22-23 PI3-kinase Pm 32 Ataxia with oculomotor apraxia AOA 9p13.3 Aprataxin Pm, Ins, Del 33, 34 Autosomal recessive spastic ataxia of ARSACS 13q11 Sacsin Pm 35 Charlevoix-Saguenay Abetalipoproteinemia ABL 4q22-24 Microsomal triglyceride Pm 37 transfer protein Ataxia with vitamin deﬁciency AVED 8q13.1-13.3 ␣-Tocopherol transfer- Pm 38 protein Refsum’s disease PHAX 10pter-p11.2 Phytanoyl-CoA hydroxylase Pm, Del, Ins 39 Cerebrotendinous xanthomatosis CTX 2q33-qter Sterol 27-hydroxylase Pm 40 Spinocerebellar ataxia, non- SCAR1 9q34 Unknown Unknown 41, 42 Friedreich Spinocerebellar ataxia with blindness SCABD 6p23-21 Unknown Unknown 41 and deafness Infantile onset spinocerebellar ataxia IOSCA 10q24 Unknown Unknown 43

AD, autosomal dominant; AR, autosomal recessive; Del, deletion; Ins, insertion; mat, maternal (mitochondrial) transmission; Pm, point mutation; Trinuc, trinucleotide-repeat expansion; X, X-chromosomal.

FTD is neuropathologically heterogeneous, and only is in childhood or adolescence. However, milder variants about 20% of patients with this disorder have the classic, with later disease onset have been described in almost all argentophilic, intraneuronal inclusions (Pick bodies). disorders. Therefore, recessive ataxias have to be con- Clinically, the FTD phenotype is defined as a neurobe- sidered in the work-up of patients with adult-onset spo- havioral entity with a unique lobar, topographic distri- radic ataxia of unknown origin. bution that is accompanied by tau pathology in most In eight disorders (Friedreich’s ataxia, ataxia telangi- cases.25 About half of FTD is inherited, usually in an ectasia, autosomal recessive ataxia with oculomotor autosomal dominant fashion. Only a small percentage apraxia, autosomal recessive spastic ataxia of Charle- (Ͻ10%) of patients with this syndrome have been linked voix-Saguenay, abetalipoproteinemia, ataxia with iso- to chromosome 17 (FTDP-17). Mutations in the gene for lated vitamin E deficiency, Refsum’s disease, and cere- MAPtau on chromosome 17 have been identified in some brotendinous xanthomatosis), the affected gene and the of these families.26 Clinical variability is present in some causative mutations have been identified, while in three pedigrees as illustrated in a family described under the disorders (autosomal recessive ataxia linked to chromo- name of pallido-ponto-nigral degeneration that featured some 9q, autosomal recessive ataxia with hearing im- extrapyramidal features in the form of L-dopa unrespon- pairment and optic atrophy, infantile onset spinocerebel- sive parkinsonism.27,28 lar ataxia), only the chromosomal gene locus is known. The umbrella term “early onset cerebellar ataxia Recommendations on the Use of Genetic Testing. (EOCA)” is used to denote those recessive ataxias in On cases with a typical phenotype of frontotemporal which neither gene mutations nor chromosomal loci are dementia with or without parkinsonism and a positive known (Table 1). family history, mutational analysis can be helpful for The only recessive ataxia, in which diagnostic genetic genetic counseling purposes. At present, it is offered testing is routinely used, is Friedreich’s ataxia (FRDA), within a research setting only. Genetic counseling before a trinucleotide repeat disorder. In most other recessive the test needs to be performed to weigh the possible ataxias, allelic heterogeneity makes routine molecular benefits and risks for the individual and the family, in the genetic testing difficult. However, simple and reliable absence of any therapeutic options in this disorder (see biochemical tests are available for several recessive also General Overview). forms. AUTOSOMAL-RECESSIVE ATAXIAS Friedreich’s Ataxia (FRDA) FRDA is the most frequent recessive ataxia. It is Thomas Klockgether characterized by onset in adolescence, progressive gait The recessive ataxias are a heterogeneous group of and limb ataxia, dysarthria, lower limb areflexia, loss of autosomal recessively inherited disorders that are char- proprioception, and cardiomyopathy. Ninety-six percent acterized by progressive ataxia. In general, disease onset of FRDA patients are homozygous for a GAA repeat

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 9 expansion in the first intron of the X25/frataxin gene.29 Autosomal Recessive Ataxia with Oculomotor Normal repeat length ranges from 6 to 36 units, whereas Apraxia (AOA) expanded alleles have 90 to 1,300 repeats. Age of onset AOA is a rare, autosomal recessively inherited ataxia is inversely correlated with the size of the shorter al- caused by various mutations in a gene coding for a novel lele.30 The remaining patients are heterozygous for the protein named aprataxin. The neurological presentation GAA expansion and a point mutation in the frataxin of AOA is variable. The gene has been simultaneously gene. Point mutations include truncating and missense found by two research groups, one studying Portuguese mutations.31 Systematic clinical studies showed that 20 families with an AT-like neurological phenotype includ- to 30% of patients homozygous for the GAA repeat ing progressive ataxia, oculomotor apraxia, and periph- expansion have atypical clinical features with disease eral neuropathy, and another studying Japanese families onset after the age of 25 years or preservation of muscle with ataxia and hypalbuminemia.33,34 In contrast to AT, reflexes.30 neoplasias and recurrent infections are not increased in AOA. Recommendations on the Use of Genetic Testing. Recommendations on the Use of Genetic Testing. Genetic testing for FRDA is widely available. The test is useful to confirm diagnosis in patients with the typical Currently, genetic tests for AOA are not routinely phenotype of FRDA. The length of expansion should not offered. be used for individual prognosis, given the large scatter- Autosomal Recessive Spastic Ataxia of ing of points along the correlation curve. Genetic testing Charlevoix-Saguenay (ARSACS) for FRDA can also be useful as part of a diagnostic screen in patients with otherwise unexplained progres- Autosomal recessive spastic ataxia of Charlevoix- sive ataxia if family history is compatible with autosomal Saguenay (ARSACS) is an autosomal recessive disor- recessive inheritance. Finding of a heterozygous GAA der clinically characterized by progressive ataxia and expansion in a symptomatic individual suggests the pres- spasticity. Molecular genetic studies in an isolated ence of a point mutation on the second allele. A prenatal population in the Charlevoix and the Saguenay regions test can be offered to couples who have already one child of Que´bec, Canada, identified causative mutations in a suffering from FRDA. Genetic counseling to weigh the novel gene encoding a large protein named sacsin option of terminating the pregnancy of a fetus bearing containing a heat-shock domain.35 The most frequent the FRDA mutation is crucial (see also General mutation accounting for more than 90% of all muta- Overview). tions is a deletion leading to protein truncation. Link- age to the same locus was established in a Tunisian 36 Ataxia Telangiectasia (AT) family with a similar phenotype. At present, it is not known how frequent ARSACS is outside the Charle- AT is an autosomal recessively inherited multisystem voix and the Saguenay regions of Que´bec, Canada. disorder characterized by cerebellar ataxia with an onset in early childhood, oculocutaneous teleangiectasias, a Recommendations on the Use of Genetic Testing. high incidence of neoplasia, radiosensitivity, and recur- Currently, genetic tests for ARSACS are not routinely rent infections. The gene affected in AT, ATM, encodes offered. a member of the phosphoinositol-3 kinase family involved in cell cycle checkpoint control and DNA re- Abetalipoproteinemia 32 pair. More than 200 distinct mutations distributed over Abetalipoproteinemia is an autosomal recessively in- the entire gene have been reported suggesting that most herited disorder characterized by onset of diarrhea soon patients carry unique mutations. after birth and slow development of ataxia, limb weak- ness, disturbed sensation, and retinal degeneration there- Recommendations on the Use of Genetic Testing. after. Abetalipoproteinemia is caused by mutations of the Because genetic testing requires sequencing of the gene encoding a subunit of a microsomal triglyceride entire ATM gene, it should be restricted to cases in transfer protein.37 The mutations include point muta- which the diagnosis cannot be made by biochemical tions, deletions, and insertions. As a consequence, circu- tests. The most useful test is determination of serum lating apolipoprotein-B–containing lipoproteins are al- ␣-fetoprotein, which is elevated in 90% of AT patients. most completely missing, and the patients are unable to In addition, radiosensitivity testing in cultured fibroblasts absorb and transport fat and fat-soluble vitamins. The is offered by specialized laboratories. neurological symptoms are due to vitamin E deficiency.

Movement Disorders, Vol. 18, No. 1, 2003 10 T. GASSER ET AL.

Recommendations on the Use of Genetic Testing. tified in certain populations. The principal way to estab- Genetic testing for abetalipoproteinemia is not rou- lish a diagnosis of cerebrotendinous xanthomatosis is tinely used. The diagnosis is made by lipid electrophore- determination of serum cholestanol. Ͻ sis showing low serum cholesterol ( 70 mg/dl) and Autosomal Recessive Ataxia Linked to nearly absent very low-density lipoproteins. In addition, Chromosome 9q blood smears show acanthocytosis, and serum vitamin E levels are reduced. However, these latter findings are not Recently, linkage to chromosome 9q was demon- specific for abetalipoproteinemia. strated in a consanguineous Japanese family with ataxia associated with elevated levels of serum creatine kinase, Ataxia with Isolated Vitamin E Deficiency (AVED). ␥-globulin, and ␣-fetoprotein.41 Another family with the Ataxia with isolated vitamin E deficiency (AVED) is clinical phenotype of ataxia with oculomotor apraxia was 42 an autosomal recessively inherited disorder with a phe- mapped to the same chromosomal region. A genetic notype resembling FRDA. AVED patients carry ho- test for this disorder is not available. ␣ mozygous mutations of the gene encoding -tocopherol Autosomal Recessive Ataxia with Hearing transport protein, a liver-specific protein that incorpo- Impairment and Optic Atrophy rates vitamin E into very low-density lipoproteins.38 As a Linkage to chromosome 6p was demonstrated in an consequence, vitamin E is rapidly eliminated. Israeli family with early-onset recessive ataxia. Patients Recommendations on the Use of Genetic Testing. subsequently developed hearing impairment and optic 41 Genetic tests are of no practical importance. The di- atrophy. A genetic test for this disorder is not available. agnosis is made by determining serum vitamin E levels. Infantile Onset Spinocerebellar Ataxia (IOSCA) Refsum’s Disease IOSCA is an early onset recessive ataxia linked to a locus on chromosome 10q that has been described in Refsum’s disease is due to mutations in the gene Finnish families. The disease manifests around the age of encoding phytanoyl-CoA hydroxylase that is involved in one year as acute or subacute clumsiness, athetoid move- the ␣-oxidation of phytanic acid.39 The clinical pheno- ments in hands and face, hypotonia, and loss of deep type of Refsum’s disease is caused by accumulation of tendon reflexes in the legs. Ophthalmoplegia and a sen- phytanic acid in body tissues. Clinically, Refsum’s dis- sorineural hearing deficit are found by school age, sen- ease is characterized by ataxia, demyelinating sensori- sory neuropathy and optic atrophy by the age of 10 to 15 motor neuropathy, pigmentary retinal degeneration, years, and female hypogonadism and epilepsy by the age deafness, cardiac arrhythmias, and ichthyosis-like skin of 15 to 20 years.43 A genetic test for this disorder is not changes. available. Recommendations on the Use of Genetic Testing. Other Forms of Early Onset Cerebellar Ataxia Genetic tests are of no practical importance. The di- (EOCA) agnosis is made by determining serum phytanic acid EOCA is used to denote those ataxias with an onset levels. before the age of 25 years in which the etiology is Cerebrotendinous Xanthomatosis unknown. Apart from cerebellar ataxia, patients may present with a variety of additional symptoms including Cerebrotendinous xanthomatosis is an autosomal re- retinal degeneration (Hallgren syndrome), hypogonad- cessive lipid storage disorder with accumulation of cho- ism (Holmes syndrome), optic atrophy (Behr syndrome), lestanol and cholesterin in various tissues. The disorder cataracts and mental retardation (Marinesco-Sjo¨gren is due to different mutations (substitutions, deletions, and syndrome), and myoclonus (Ramsay Hunt syndrome). insertions) of the gene encoding cholestanol 27-hydrox- Genetic or biochemical tests for these disorders are not ylase.40 The clinical syndrome includes xanthomatous available. swelling of the tendons, cataracts, and a slowly progressive neurological syndrome including ataxia, pyramidal AUTOSOMAL-DOMINANT CEREBELLAR signs, and cognitive decline. ATAXIAS Recommendations on the Use of Genetic Testing. Alexandra Du¨rr The diversity of mutations make genetic testing diffi- Autosomal dominant cerebellar ataxias are genetically cult. However, common gene mutations have been iden- and clinically heterogeneous. Clinical heterogeneity is

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 11

TABLE 2. Classiﬁcation of autosomal dominant cerebellar ataxias

Proportion Pathological Gene Locus of SCAs repeat sizes Particularities Ref. Genes identiﬁed SCA1 6p23 5–40% 39–83 44 SCA2 12p24 10–40% 32–77 45 SCA3 14q32 11–84% 54–89 Machado-Joseph disease 46 SCA6 19p31 1–16% 20–33 ␣1 subunit calcium channel 47 SCA7 3p12 5–8% 37–306 Ataxia and progressive macular dystrophy 48 SCA10 22q13 3 families ATTCTa Ataxia and epilepsy 49 SCA12 17 2 families 55–78a PPP2R2B gene 50 DRPLA 14 Rare 39–83 Atrophin 51 TBP (SCA 17) Rare 44–63 Very severe phenotype 52 Genes not yet identiﬁed SCA4 16q 1 family 53 SCA5 11cen 2 families 54 SCA8 13q21 1 family Ͼ107a CTG repeat: pathological or polymorphism? 55 SCA11 15q 1 family 56 SCA13 19 1 family Ataxia and mental retardation 57 SCA14 19 1 family 58 SCA16 8q 1 family Ataxia and head tremor 59

aNon-coding repeat. reflected by the pattern of atrophy on cerebral imaging, overlap among different SCAs makes prediction of the which varies from typical olivo-ponto-cerebellar atrophy molecular origin impossible and emphasizes the usefulness to isolated atrophy of the cerebellum. The mapped genes of molecular analysis. However, each entity has particular- are designated SCA (spinocerebellar ataxia) 1 to 8, ities that are related to the gene involved, to the size of the SCA10 to 17, and DRPLA (dentatorubropallidoluyisian expansion, and to the disease duration but often they are not atrophy). SCA17 is a complex syndrome of cerebellar specific enough to be clinically useful (Table 3). The rela- ataxia and intellectual deterioration associated with a de tive frequency of the different SCAs varies markedly novo expansion of a CAG repeat in the TATA box among countries, both within Europe and in other parts of binding protein (TBP) gene. Nine genes have been iden- the world, but SCA3 (Machado-Joseph disease) is the most tified, reflecting a marked genetic heterogeneity (Table frequent gene in most populations. 2). Except for SCA8, in which the causative mutation remains a matter of debate, the same molecular mecha- Pitfalls in Molecular Analysis nism appears to underlie the disease process in all SCAs: the expansion of a CAG trinucleotide repeat in the cod- In most instances, there is a clear-cut difference in the ing sequence of the involved genes resulting in a poly- size of normal and pathological alleles, which allows glutamine expansion in the corresponding protein. their unambiguous identification in molecular testing. SCA12 is an exception, as the gene harbors a trinucle- However, there is some overlap at the SCA1 and SCA2 otide expansion in the non-coding region (similar to loci where normal repeats in the pathological range up to Friedreich’s ataxia or myotonic dystrophy). 44 and 34 units were observed, respectively. Fortunately, The clinical and pathological heterogeneity that is found sequencing these large normal repeats should allow them even among affected members of the same family makes to be distinguished from pathological expansions be- accurate clinical diagnosis difficult. In addition, the clinical cause large normal CAG repeats are interrupted, by one

TABLE 3. Phenotype-genotype correlation in autosomal dominant cerebellar ataxias

CAG repeat expansion Small Medium Large SCA1 Cerebellar ataxia, increased reﬂexes Amyotrophic lateral sclerosis-like SCA2 Postural tremor Cerebellar ataxia, decreased reﬂexes Cerebellar ataxia, chorea, dementia (Huntington’s disease–like) SCA3 Axonal neuropathy, parkinsonism Cerebellar ataxia, gaze-evoked nystagmus SCA6 Episodic ataxia-like Pure cerebellar ataxia SCA7 Cerebellar ataxia without visual loss Cerebellar ataxia, macular degeneration Visual loss before cerebellar syndrome SCA17 Cerebellar ataxia, dementia, chorea Mental retardation, short stature

Movement Disorders, Vol. 18, No. 1, 2003 12 T. GASSER ET AL. or more CAT in SCA1 and CAA in SCA2, whereas tween the two conditions (absence of prevention or pathological ones are made of pure CAG repeats. treatment), intensive pre-test and post-test counseling and psychological support is necessary as stated Recommendations on the Use of Genetic Testing. above. Genetic counseling should accompany molecular test- 4. Exclusion of the SCA mutations and loci in familial ing in each patient and be offered to relatives after the cerebellar ataxia does not exclude the presence of a identification of a SCA mutation. mutation in an as yet unknown gene. Therefore, negative genetic testing does not rule out autosomal dom- 1. Screening for CAG expansion in known genes will inant transmission and requires appropriate genetic identify the responsible gene in more than 60% of the counseling. families with autosomal dominant cerebellar ataxia in a European population. This proportion varies in dif- WILSON DISEASE ferent populations: in Japan, for example, about 80% of all dominant SCAs are explained by identified Thomas Gasser genes. In some instances, the strategy for molecular Wilson disease is a disorder of copper metabolism that testing can be guided by the frequency of the mutation can present with neurological, hepatic, or psychiatric in the population (Table 2) or by the clinical picture disturbances, or a combination thereof. Neurological pre- (Table 3). For instance, most Portuguese patients sentations include movement disorders (tremor, dysto- carry the SCA3/MJD mutation and most Italian cases nia, dysarthria, bradykinesia, choreoathetosis). Psychiat- are accounted for by SCA1 or SCA2. The relative ric disturbances include depression, disorganization of prevalences of MJD/SCA3, SCA6, and DRPLA are personality, and, occasionally, intellectual deterioration, significantly higher in Japanese (43%, 11%, and 20%, while hepatic involvement manifests as acute and respectively) than in Caucasian patients (30%, 5%, chronic hepatitis leading to cirrhosis and liver failure. and 0%, respectively). The occurrence of the different The worldwide prevalence of Wilson disease is esti- SCAs in various parts of the world has been found to mated to be of the order of 30 per 1 million, with a gene correlate with the size of the respective CAG-repeat, frequency of 0.56% and a carrier frequency of 1 in 90. from which pathologic expansions arise, in the pop- Wilson disease is caused by mutations in the gene for ulations in question.60 a copper-transporting p-type ATPase, called ATP7B,62,63 Clinically, the association of cerebellar ataxia and located on chromosom13q14-q21. Based on experiments vision loss is very specific of SCA7, other clinical in animal models, it is likely that the ATP7B protein may clues are less helpful. When all known genes are function in the copper transport coupled with the synthe- excluded linkage analyses for other mapped loci can sis of ceruloplasmin in the Golgi apparatus.64 Its function only be performed in very large families but this is not is essential for biliary excretion of copper. usually done in clinical practice. The ATP7B gene is a large gene with an open 2. In sporadic cases with adult onset the mutation re- reading frame of more than 10,000 bp. More than 170 sponsible for Friedreich’s ataxia is more frequent than mutations have been described so far, most being point those for the various SCAs. The frequency of isolated mutations or small deletions (see mutation database cases with known SCA mutations ranges from 2 to online: www.medgen.med.ualberta.ca/database.html). 7% depending on the population.61 Most isolated There is a rough relationship between genotype and cases, which turned out to be SCA, are explained by phenotype: mutations leading to a complete abolition of the following reasons: 1) censured history, because of ATP7B function (early stop mutations, mutations in early death of the transmitting parent, adoption or highly conserved and functionally important regions) false paternity, 2) still asymptomatic parent because lead to an early and predominantly hepatic dysfunction, of anticipation (particularly in SCA7), 3) false diag- whereas point mutations in less important regions of the nosis in affected relatives not verified by clinical gene are associated with later onset and a predominance examination (multiple sclerosis for instance), or 4) of neurological and psychiatric symptoms.65 There is de-novo mutation (SCA7, TBP). only one mutation that occurs with a fairly high fre- 3. Presymptomatic testing for unaffected at-risk individ- quency in a mixed Caucasian population, H1059Q. A uals and prenatal testing can be offered in families mean age of onset of 20 to 22 years in patients homozy- with identified mutations. As shown by the 10 years gous for this mutation has been described.66,67 experience of presymptomatic testing in Huntington’s Generally, the diagnosis of WD in a symptomatic disease and because of the obvious similarities be- individual relies upon demonstration of abnormal copper

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 13 indices, including low serum ceruloplasmin, high urinary Czech descent and subsequently confirmed in three other copper and/or increased hepatic copper content, and the American families. The locus on chromosome 3 (FET1) demonstration of a Kayser-Fleischer ring of the cornea. was found in 16 small Icelandic families affected with a similar ET phenotype.76 These studies suggest that there Recommendations on the Use of Genetic Testing. is nonallelic genetic heterogeneity causing the “pure” ET Mutational analysis of the ATP7B gene is available on a phenotype. limited basis only. Some laboratories offer detection of the H1096Q mutation and a few others of the more common Recommendations on the Use of Genetic Testing. sequence alterations. Due to the large size of the gene, Because the genes that cause ET are not known, ge- however, it is usually not feasible to sequence the entire netic testing for ET is not currently available. However, coding region. Therefore, failure to detect one of the common mutations does not rule out the diagnosis and is not genetic research studies are being conducted in families helpful for management and genetic counseling. with dominantly inherited ET. “Indirect” genetic diagnosis (see General Overview) can be considered for the early diagnosis and treatment PRIMARY TORSION DYSTONIA of at-risk sibs of an individual affected with Wilson Susan B. Bressman disease. Markers within and flanking the gene must be typed to exclude recombinations. If the markers are There are many genetic causes for dystonia and they informative (i.e., they allow to discriminate between the are divided into two categories: primary (or idiopathic) two parental chromosomes), it is possible to determine and secondary (see Table 4).77 Secondary dystonia has whether a clinically healthy sibling of an affected carries always been recognized as a broad category containing one or both of the affected chromosomes. This informa- many different disorders, whereas primary dystonia ini- tion allows the institution of early treatment in homozy- tially denoted a unitary state of pure dystonia of un- gotes and genetic counseling of the heterozygous carrier known (but possibly genetic), origin. To diagnose pri- (at an estimated carrier rate of 1/90 in the general pop- mary dystonia required: 1) no exogenous or acquired ulation, the risk that a carrier would marry another carrier etiology (e.g., trauma, neuroleptic intake, birth asphyxia); 2) and have an affected child is one in 360). Prenatal testing no suspicion of a degenerative or inherited disorder with is possible when linkage studies are informative. In this associated pathological or neurochemical changes (e.g., case, careful counseling again is crucial to discuss dif- Hallervorden Spatz, Wilson’s disease, Parkinson’s disease); ferent options, including the termination of a pregnancy and 3) aside from tremor, no physical/neurological signs on the basis of genetic testing in WD, particularly con- other than dystonia. Although these criteria continue to sidering the potential treatability of the disease when distinguish primary from secondary dystonia, primary dys- diagnosed early. tonia is no longer a single entity, and at least to some extent ESSENTIAL TREMOR it is no longer a diagnosis of exclusion. As loci and genes are identified, and their functions clarified, the distinction Joseph J. Higgins between primary and secondary dystonia is blurring. Pri- ET is one of the most common neurological conditions mary dystonia as a group of disorders, many of genetic in humans with an overall prevalence ranging between etiology, is emerging. 4.1 to 39.2 cases per 1,000 persons.68 Although the The clinical spectrum of primary dystonia is remark- disorder is prevalent, little is known about its pathogen- ably variable, but there is a clustering of key clinical esis. Studies using positron emission tomography in hu- features suggesting distinct genetic subgroups. The age mans provide evidence for a central nervous system at onset distribution is bimodal, with a peak at age 9 etiology for ET by demonstrating an increase in glucose (early onset) and 45 (late onset), divided by a nadir at age utilization of the olivocerebellar pathway.69 27.78 Moreover, there is a relationship between the age at Most cases of ET are familial,70,71 and most often onset of symptoms, body region first affected, and clin- described as an autosomal dominant trait with high, but ical progression of signs. When primary dystonia begins not full penetrance.72,73 in childhood or adolescence, it often starts in a leg or Loci in families with “pure” ET have been mapped to arm, and then progresses to involve multiple body re- the short arm of chromosome 2 and the long arm of gions; when it begins in adult years, symptoms first chromosome 3.74–76 The locus on chromosome 2 (ETM) involve the neck, cranial, or arm muscles, and dystonia was initially identified in a large American family of tends to remains localized.79

Movement Disorders, Vol. 18, No. 1, 2003 14 T. GASSER ET AL.

TABLE 4. Molecular classiﬁcation dystonia

Gene Locus Particularities Ref. DYT1 9q34 Early limb-onset primary torsion dystonia; autosomal dominant with 30% penetrance; gene 80 encodes torsinA; all identified mutations are a GAG deletion DYT2 ? Autosomal recessive in Gypsies DYT3 Xq13.1 X-linked dystonia parkinsonism (known as XDP or Lubag); almost all due to founder 108 Filipino mutation; young adult-onset, cranial (including larynx/stridor) and limb dystonia, parkinsonism develops (or at onset) with shuffling, drooling DYT4 ? Whispering dysphonia in Australian family; autosomal dominant 109 DYT5 14q22.1 Childhood-onset dopa-responsive dystonia (DRD) and parkinsonism; autosomal dominant 95 with sex influenced reduced penetrance (higher in girls); gene encodes GTP cyclohydrolase1, many different mutations DYT6 8p Adolescent and early adult-onset, mixed phenotype with limb, cervical and cranial onset 91 and both limited and generalized spread; thus far only found in Mennonite families; autosomal dominant reduced penetrance DYT7 18p Late-onset primary cervical dystonia in North German families, autosomal dominant with 92 reduced penetrance DYT8 2q Paroxysmal non-kinesigenic choreoathetosis (PNKC); autosomal dominant 110 DYT9 1p Episodic choreoathetosis with spasticity (CSE), autosomal dominant 93 DYT10 16p11 Paroxysmal kinesigenic dystonia (PKC) 111 DYT11 7q21 Myoclonus-dystonia, autosomal dominant childhood-onset dystonia (esp. limbs and neck) 107 and myoclonus (esp. neck, shoulders, face), often better with alcohol, caused by mutations in the gene for ε-sarcoglycan DYT12 19q Rapid-onset dystonia-parkinsonism (RDP), autosomal dominant with reduced penetrance 112 DYT13 1p36 Adult-onset dystonia with predominant cervical and upper-limb distribution 113

DYT1 and Earl y-Onset PTD (Also Termed primary dystonia, regardless of family history. Many Dystonia Musculorum Deformans) cases (probably ϳ50%) will be due to DYT1. One form of early-onset primary dystonia (DYT1), Genetic testing is commercially available and should which is transmitted in an autosomal dominant fashion be considered the first diagnostic test to apply to: 1) all with reduced (30–40%) penetrance, is caused by the PTD patients, whether Ashkenazi or non-Jewish, with deletion of one of a pair of GAG codons in a gene on onset before the age 26 years and 2) PTD patients with chromosome 9q34, called TorsinA.80 This is the only later onset who have a related family member with early Ͻ 85 disease mutation in this gene identified to date. It has ( 26 years) onset. The specificity of using age 26 as a been found in families of diverse ethnic background,81–84 cut-off is higher in Ashkenazi Jews (63%) than non-Jews and analyses of haplotypes indicate that deletions origi- (43%); further, specificity can be greatly increased by nated from multiple independent mutation events. restricting testing to those with limb-onset. However, The clinical expression of the DYT1 GAG deletion is sensitivity then decreases to about 95%. Genetic coun- generally similar across ethnic groups.82,83,85,86 The great seling, prior to molecular testing, has to take these lim- majority of people with dystonia due to the DYT1 GAG itations into account. deletion have early onset and all clinically ascertained cases reported to date have onset before age 26 years. Late-Onset PTD One or more limbs are almost always affected and over Late-onset PTD is genetically more complex than 95% have an affected arm.85 The DYT1 GAG-deletion is early-onset. Like early-onset primary dystonia, late-on- more important in the Ashkenazi population, where it set, focal, or cervical-cranial primary dystonia also may accounts for about 90% of early limb-onset cases, due to be inherited in an autosomal dominant fashion.87–90 a founder effect; this compares with non-Jewish people, However, unlike early-onset dystonia, most studies show where only 50–65% of early limb-onset PTD has the that penetrance is even more reduced (about 12–15% mutation.80,82,86 compared to 30% for early-onset). Alternatively, penetrance may be higher in a genetic subset with the Recommendations on the Use of Genetic Testing. remainder being non-genetic. Because of the reduced penetrance and variable ex- Two additional PTD loci have been mapped: DYT6 on pression of primary dystonia, with mild cases going chromosome 8 was identified in two families of Menno- undiagnosed, it is not uncommon to obtain a negative nite and Amish origin.91 The phenotype in these families family history. Based on current findings it is not unrea- is “mixed” in that age-at-onset is relatively early (mean, sonable to assume a genetic etiology for most early-onset 18 years; range, 6–38 years), but unlike most early-onset

Movement Disorders, Vol. 18, No. 1, 2003 REVIEW: DIAGNOSIS OF INHERITED MOVEMENT DISORDERS 15 primary dystonia, the cervical or cranial muscles are prominent psychiatric abnormalities, including panic at- affected first in about one half. tacks and obsessive-compulsive behavior.102,103 In the Another locus (DYT7) was mapped in a Northwest majority of MDS families, the disease is linked to a locus German family affected primarily with late-onset torti- on chromosome 7q21,104–106 and different heterozygous collis, although mild facial and arm involvement was loss-of-function mutations in the gene for ⑀-sarcoglycan, noted in one affected, as was spasmodic dysphonia.92 which maps to this area, have been identified.107 Pen- The DYT7 gene localizes to a 30 cM region on chromo- etrance of the mutations is reduced, particularly if the some 18p between D18S1153 and 18pter.92,93 The extent disease allele is inherited from the mother, suggesting a to which DYT6 and DYT7 account for adult and cervi- maternal imprinting mechanism.107 cal/cranial-onset primary dystonia remains unclear as there is evidence indicating other as yet unmapped loci.94 Recommendations on the Use of Genetic Testing. Genetic testing for MDS is presently available only on Recommendations on the Use of Genetic Testing. a research basis. The genetic contribution for most adult-onset PTD remains to be clarified and genetic counseling for the Other Forms of Dystonia adult-onset group needs to reflect this. At present, there In other forms of dystonia, such as the paroxysmal is no testing for PTD loci other than DYT1, although in dystonias or “rapid-onset dystonia–parkinsonism,” genes sufficiently large families linkage to DYT6 or DYT7 have been mapped but not cloned, and molecular diag- may be performed on a research basis. nosis is not available.

Dopa-Responsive Dystonia OTHER GENETIC DISEASES A rarer variant of primary dystonia, dopa-responsive ASSOCIATED WITH A VARIETY OF dystonia caused by point-mutations in the gene for GTP- MOVEMENT DISORDERS cyclohydrolase I (GCHI) in the majority of cases.95 Again, the phenotype is usually characterized by a child- Thomas Gasser hood onset dystonia, affecting the extremities first, but Genes for an increasing number of other inherited rarely, craniocervical dystonia may be the only manifes- diseases associated with a variety of movement disor- tation. As a large number of different mutations have ders, which do not easily fit into one of the above been described that are scattered over the entire gene categories, but may nevertheless represent important en- (and could not even be detected in all cases within the tities, are being mapped and cloned. coding region), the practical role of molecular diagnosis is limited. Fortunately, a suspicion of dopa-responsive Neurodegeneration with Brain-Iron dystonia can usually be confirmed by the excellent re- Accumulation Type 1 sponse to L-dopa treatment, so that molecular analysis is Neurodegeneration with brain-iron accumulation type frequently not necessary. 1 (NBIA-1, formerly called Hallervorden-Spatz syn- A recessive form of dopa-responsive dystonia has drome) is an autosomal recessive disorder, usually pre- been described in patients with a genetic deficiency of senting during childhood or early adolescence with a tyrosine-hydroxylase (TH).96,97 From the few cases that complex movement disorder with elements of dystonia, have been described in the literature, the phenotype spasticity, and parkinsonism. Progressive dementia and appears to differ considerably from that in dopa-respon- epileptic seizures are also a part of the clinical picture. sive dystonia caused by GCH-1 mutations, and includes Characteristic iron accumulation in the basal ganglia, hypokinetic-rigid symptoms98 and spastic paraplegia99 visualized as hypointensities on MR, is seen. The gene beginning in infancy. has been mapped to chromosome 20, and has recently been identified as the gene for pantotenate kinase 2 Myoclonus–Dystonia Syndrome (PANK2), encoding a crucial enzyme of coenzyme A- Myoclonus–dystonia syndrome (MDS, DYT11) is an synthesis. Interestingly, the associated phenotype ap- autosomal-dominant disorder characterized by bilateral, pears to be broader than typical NBIA-1, as several cases alcohol-sensitive myoclonic jerks, involving predomi- with atypical presentations or later age of onset have nantly the arms and axial muscles. Dystonia, usually been found to carry mutations.114 torticollis and/or writer’s cramp, occurs in most, but not Another complex neurodegenerative phenotype that is all affecteds, and may occasionally be the only symptom being unraveled by cloning the responsible genes is of the disease.100,101 In addition, patients often show neuroacanthocytosis. This syndrome is characterized by

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